Loss of integrin αvβ6-mediated TGF-β activation causes Mmp12-dependent emphysema

Integrins are heterodimeric cell-surface proteins that regulate cell growth, migration and survival. We have shown previously that the epithelial-restricted integrin alphavbeta6 has another critical function; that is, it binds and activates latent transforming growth factor-beta (TGF-beta)(1,2). Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)-a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema(3). Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta6 integrin subunit that support TGF-beta activation, or by the loss of Mmp12. Furthermore, we show that the effects of Itgb6 deletion are overcome by simultaneous transgenic expression of active TGF-beta1. We have uncovered a pathway in which the loss of integrin-mediated activation of latent TGF-beta causes age-dependent pulmonary emphysema through alterations of macrophage Mmp12 expression. Furthermore, we show that a functional alteration in the TGF-beta activation pathway affects susceptibility to this disease.